Exogenous choline is known to be required for acetylcholine (ACh) synthesis and to be supplied to cholinergic neurons, as choline or one of its precursors, from a variety of sources (e.g., circulation, breakdown of released ACh, efflux of free choline from the intra-cellular space of brain cells, hydrolysis of choline-containing membrane phospholipids). There are many diseases in which acetylcholine production and/or release appear to be affected. For example, Alzheimer's Disease is accompanied by a cholinergic defect in specific areas of the brain. A specific defect in choline acetyltransferase, the enzyme which catalyzes acetylcholine production from choline and acetyl-coenzyme A, has been identified in autopsy material from patients with Alzheimer's Disease. Summers, W. K. et al., The New England Journal of Medicine, 315:1241-1245 (1986) Davies, P. and Maloney, A. J. F., Lancet, 2:1403 (1976). Loss of cholinergic function is believed to contribute to the intellectual impairment, memory deficits and dementia which characterize Alzheimer's Disease. A. Enz, "Accumulation and Turnover of Ach After ACHE-I in Rat Brain", In: Advances in Alzheimer Therapy: Cholinesterase Inhibitors, An International Symposium, March 1988. Cholinergic deficiency states are also believed to be the basis for other neurological disorders. For example, it is thought that cholinergic deficiency states are present in such neurological disorders as Tourette's disease, Freidreich's ataxia, Huntington's Chorea amyelotrophic lateral scerosis, familiar dysautonomia, post-stroke, post-traumatic, or post-toxic syndromes affecting memory of cognition and tardive dyskinesia. S. Bajada, Alzheimer's Disease: A Report of Progress. In: Aging, S. Corkin, et al., (ed.) 9:427, Raven Press, New York, N.Y. (1982).
At least in part because of the evidence that a cholinergic defect (apparently low acetylcholine synthetic enzyme concentrations) is present in patients with Alzheimer's disease and that cholinergic mechanisms have a role in learning and memory, treatments have been devised in which choline or one of its precursors is administered in an attempt to counteract the acetyl choline deficiency. S. Bajada, Alzheimer's Disease: A Report of Progress In: Aging, S. Corkin, et al., (ed.) 9:427 Raven Press, New York, NY (1982). Drugs which inhibit the action of cholinesterase, such as physostigmine and tetrahydroaminoacridine (THA), have also been used in treating Alzheimer's patients. Kaye et al., Alzheimer's Disease: A Report of Progress, In: Aging, S. Corkin, et al., (ed.) 9:433 Raven Press, New York, N.Y. (1982); Summers, et al., New England Journal of Med., 315(20): 1241-1245 (1986). However, pharmacological therapy with cholinergic agents has had only limited success in patients with degenerative neurological disorders such as is evident in Alzheimer's Disease.
It would be useful to have a means by which the adverse effects of drugs administered to treat neurological diseases or conditions could be reversed or offset, with the result that the drug could have the desired therapeutic effect without impairing important activities, such as neuronal function.